PROJECT SUMMARY Most patients with hepatocellular carcinoma (HCC) are treated with palliative liver-directed therapies; these therapies provide only modest improvements in survival and can be toxic to normal liver tissues. Many patients are not candidates for these therapies due to poor underlying liver function. Natural killer cells (NKs) constitute the first line of defense against invading infectious microbes and neoplastic cells. NKs exert an effector function independent of priming, destroying cancer cells by secreting cytotoxic lymphokines and disrupting the tumor vasculature. Adoptive transfer immunotherapy (ATI) with NK cells is a promising approach for the treatment of both hematopoietic malignancies and solid tumors. However, critical barriers must be overcome to achieve meaningful outcomes in solid tumors. A sufficient number of NK cells must migrate to tumors and infiltrate the tumor tissues to exert potent tumoricidal functions. The limited homing efficiency of NK cells to tumors tissues, following systemic administration, has inhibited clinical efficacy. HCC patients commonly undergo image-guided procedures wherein a catheter is selectively placed to deliver drugs directly into the arterial blood supply of the tumor(s). Targeted infusions afford significant reductions in systemic toxicity and delivery of potent doses of drugs and/or drug-eluting microspheres. We propose radically augmenting the homing efficiency of NK cells to HCC via a) image-guided transcatheter infusion directly into the blood supply of targeted liver tumor(s) and b) concurrent infusion of interferon-gamma (IFN-?) eluting microspheres visible in computed tomography (CT) imaging to strengthen the cytokine gradients that drive NK migration into the tumor tissues. Due to wide variations in effector cell homing efficiency, patient-specific dosimetry and prediction of tumor response can be difficult during these adoptive transfer immunotherapies. Serial in vivo monitoring of NK cell migration to tumors and local delivery of IFN-? will be critical to permit early prediction of longitudinal response thus affording timely adjustments to each individual patient's therapeutic regimen (additional NK infusion or adoption of alternative therapies as needed). We propose magnetic labeling of NK cells to permit magnetic resonance imaging (MRI) of transcatheter intra-hepatic delivery and local delivered IFN-? augmented NK cell migration to liver tumors using CT visible microspheres. Through this collaborative project building upon our strengths in materials science, molecular imaging, cancer immunology, nanomedicine and interventional oncology we seek to develop a powerful new therapeutic approach involving image-guided catheter-directed delivery of both magnetically-labeled NK cells and IFN-? eluting microspheres to liver tumors.